ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disorder worldwide, characterized by progressive fluid-filled cyst growth and enlargement of both kidneys. Current clinical management of ADPKD simply aim to treat secondary symptoms of the disease such as high blood pressure, hemorrhage, pain, and infections, and by the age of 60, half of all patients require dialysis or transplantation due to renal failure. In contrast, this proposal aims to develop a radically different approach to ADPKD treatment and management: nanotherapeutics that can be orally taken, home directly to diseased kidneys, and deliver drugs that stop the formation and expansion of renal cysts. Despite its debilitating nature, ADPKD has not benefited from any advances in nanomedicine. Part of the problem is until recently, few drugs have shown great promise to slow progression of ADPKD, and therefore it has not been a worthy endeavor to consider the development of nanoparticle formulations. However, the challenge is to effectively deliver these therapies to the disease cells without nanoparticle uptake by the liver, and without causing toxicity to normal cells over the lifetime of a chronic disease. This can be achieved by peptide amphiphile micelles (PAMs) because this custom platform can be functionalized with nearly any therapeutic including drugs already routinely used in the clinic such as metformin (type 2 diabetes), pravastatin (common statin used in heart disease), rapamycin (immunosuppressant), and everolimus (immunosuppressant) which have been recently repurposed in ADPKD; 2) in addition, micelles serve as a multifunctional platform and can also be decorated with specific peptide ligands with high avidity so that they actively localize to and are internalized by renal epithelial cells responsible for ADPKD; 3) micelles can be smaller than 10 nm to take advantage of passive targeting by renal clearance which is an enabling characteristic that is unique to our nanoparticle platform; 4) the self-assembling nature of micelles affords easy assembly of particles consisting of optimal ligand to drug ratios to form a library of multifunctional nanoformulations; 5) micelles consist of biocompatible components that allow bio-interfacing without causing cell or tissue damage, a key biocompatible property for clinical translation; and 6) micelles can be used without disturbing normal kidney function. This concept, i.e. drug delivery by nanoparticles to inhibit ADPKD is a dramatic departure from simply treating its symptoms, and will change the way we think about managing many inherited diseases and provide the framework for nanomedicine to move from bench to beside for ADPKD. Given the widespread nature of polycystic kidney disease and prevalence of dialysis and end-stage kidney disease, this work could potentially impact millions of lives and is directly relevant to the mission of the NIH. Major innovations that will be presented include: 1) the first design and testing of nanotherapeutics for ADPKD, 2) pioneering oral drug delivery strategies for nanoparticles in chronic diseases, and 3) establishing a pharmacokinetic and toxicology foundation for nanotherapeutics with repurposed drugs in ADPKD.